This proposal describes an interrelated series of clinical and preclinical investigations of a biological marker, membrane fluidity, in the study of primary degenerative dementia. Alzheimer's disease is the most common cause of dementia in the elderly, and presents a substantial and growing mental health problem. The greatest potential significance of the proposed experiments lies in what might be learned about the etiology and pathophysiology of Alzheimer's disease. It seems possible that Alzheimer's disease represents a group of illnesses with different etiologies, but with overlapping pathophysiologies that result in a similar final outcome from a clinical perspective. Platelet membrane fluidity may be the first biological marker to identify a clinically distinct subgroup of demented patients from among a cohort of patients who meet currently accepted diagnostic criteria for probable Alzheimer's disease. Our initial family studies suggest that this subgroup includes familial form(s) of Alzheimer's disease and that increased platelet membrane fluidity may antedate the onset of clinical symptoms. If confirmed, this biological marker would substantially advance genetic and environmental studies of Alzheimer's disease that are now hampered by the inability to identify affected individuals, or individuals at risk, in the absence of symptoms of dementia.